title: Effect of IN-1130, a small molecule inhibitor of transforming growth factor-beta type I receptor/activin receptor-like kinase-5, on prostate cancer cells.
abstract: OBJECTIVE
  Transforming growth factor-beta is a potent immune suppressor that is over expressed by most malignant cells to evade the host immune response. Thus, a potential anticancer therapeutic strategy is the inhibition of transforming growth factor-beta signaling.
  
  
  METHODS
  We investigated the specificity and the antitumor effect of IN-1130, a novel small molecule inhibitor of the transforming growth factor-beta type I receptor ALK-5.
  
  
  RESULTS
  IN-1130 inhibited transforming growth factor-beta induced cell death and gene transcriptional activity in a concentration dependent manner in the human hepatoma cell line HepG2. Simultaneously immunoblot analysis demonstrated that IN-1130 inhibited the Smad2 phosphorylation induced by transforming growth factor-beta. To determine the specificity of IN-1130 for transforming growth factor-beta signaling the effect on active and bone morphogenic protein signaling was subsequently investigated. Results demonstrated that IN-1130 did not inhibit bone morphogenic protein signaling. However, active signaling was blocked by IN-1130 in a concentration dependent manner. Furthermore, immunoblot analysis for phospho-Smad2 following transfection with constitutively active ALK-1 to 7 demonstrated that IN-1130 inhibited ALK-4 (active receptor type IB), 5 (TbetaRI) and 7 (nodal type I receptor). To investigate the antitumor effect of IN-1130 WT mice were injected subcutaneously with the murine prostate cancer cell line Tramp C2. Seven days later IN-1130 was administered intraperitoneally daily for 30 days. Results demonstrated a dramatic decrease in tumor volume in association with an enhanced immune response in the treatment group.
  
  
  CONCLUSIONS
  Taken together these results demonstrate that IN-1130 is a relatively nontoxic inhibitor of ALK-4/5/7 that may potentially treat prostate cancer.
authors.affiliation: Division of Urologic Oncology, Cancer Institute of New Jersey and Robert Wood Johnson Medical School, New Brunswick, New Jersey 08903, USA.
authors.forename: Geun Taek
authors.initials: GT
authors.lastname: Lee
authors.forename: Jun Hyuk
authors.initials: JH
authors.lastname: Hong
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Mueller
authors.forename: John A
authors.initials: JA
authors.lastname: Watson
authors.forename: Cheol
authors.initials: C
authors.lastname: Kwak
authors.forename: Youn Young
authors.initials: YY
authors.lastname: Sheen
authors.forename: Dae-Kee
authors.initials: DK
authors.lastname: Kim
authors.forename: Seong Jin
authors.initials: SJ
authors.lastname: Kim
authors.forename: Isaac Yi
authors.initials: IY
authors.lastname: Kim
mesh_terms: D000818:Animals; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D008297:Male; D051379:Mice; D011471:Prostatic Neoplasms / Q000473:pathology*; D011810:Quinoxalines / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects
chemical_list: C530153:3-((5-(6-methylpyridin-2-yl)-4-(quinoxalin-6-yl)-1H-imidazol-2-yl)methyl)benzamide; D007093:Imidazoles; D011810:Quinoxalines